Purpose: Use of magnetic resonance imaging (MRI)/transrectal ultrasound fusion biopsies to determine the accuracy of multiparametric MRI (mpMRI), using Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2), for detecting clinically significant prostate cancer in the overall gland and specifically the peripheral zone (PZ) and transitional zone (TZ). Methods: A retrospective analysis of patients who underwent fusion biopsy identified 137 men with 231 prostate lesions was approved by the Institutional Review Board. Subjects initially classified under PI-RADSv1 criteria were regraded using PI-RADSv2 by a radiologist blinded to PI-RADSv1 score and biopsy results. Spearman correlation, chi-squared, and logistic regression analysis were performed. Results: There was positive correlation between PI-RADSv2 and Gleason scores (P < 0.001). In the PZ, mpMRI demonstrated 100% sensitivity, 100% negative predictive value, and 35.9% positive predictive value, compared to 100%, 100%, and 27.1%, respectively, for TZ lesions. When predicting clinically significant prostate cancer, the PI-RADSv2 area under the curve for TZ lesions was 0.844 (95% CI: 0.753-0.935, P < 0.001) and 0.769 (95% CI: 0.684-0.854, P < 0.001) for PZ lesions. Combining PI-RADSv2 with additional risk factors (body mass index, prostate-specific antigen density, digital rectal examination) improved the area under curve. Conclusions: PI-RADSv2 achieves excellent sensitivity and negative predictive value for both PZ and TZ lesions.